G protein-coupled receptor kinase (GRK) is an enzyme for phosphorylation and desensitization of G protein-coupled receptors (GPCR) activated by an agonist. Research on the physiological functions of members of the GRK family has been conducted primarily focusing on a member of that family in the form of β adrenergic receptor kinase 1 (βARK1=GRK2) and on a member of the GPCR family in the form of β adrenergic receptor (βAR). Although there are reports suggesting that GRK is involved in the formation of the pathology of various diseases, the relationship between cardiac βAR phosphorylation and desensitization by βARK1 and the pathology of heart failure has been the subject of the greatest research.
In the heart of a patient with heart failure, it is well known that the expressed amount of βARK1 mRNA increases remarkably and desensitization of cardiac βAR occurs (see, for example, Non-Patent Documents 1 and 2). A similar result has been obtained in various animal models of heart failure, and it's believed that cardiac βAR phosphorylation and desensitization by βARK1 is a causative factor of exacerbating the pathology of heart failure.
Since βARK1 is activated as a result of being translocated to the cell membrane by bonding Gβγ and the C terminal thereof, the preventive and therapeutic effects on the pathology of heart failure by inhibition of βARK1 can be examined by expressing the C terminal of βARK1 (βARKct: peptide composed of the 495th to 689th amino acids) as dominant negative βARK1 in the hearts of various heart failure animal models. For example, improvement of cardiac function by introduction of βARKct into the hearts of a rabbit post-myocardial infarction heart failure model (see, for example, Non-Patent Documents 3 and 4), the suppression of the onset of heart failure in muscle LIM protein knockout (MLP−/−) mice by crossing a dilated cardiomyopathy model in the form of MLP−/− mice with βARKct transgenic mice (see, for example, Non-Patent Document 5), the suppression of reduction of cardiac function and death in calsequestrin (CSQ) transgenic mice by crossing a dilated cardiomyopathy model n the form of CSQ transgenic mice with βARKct transgenic mice (see, for example, Non-Patent Document 6), and the suppression of death due to post-myocardial infraction heart failure in βARKct transgenic mice (see, for example, Patent Document 1) have been previously reported. Thus, βARK1 inhibitors are thought to be promising as preventives and therapeutics for heart failure.
However, although there have been some reports thus far relating to compounds having βARK1 inhibitory activity (see, for example, Non-Patent Document 7 and Patent Documents 2 to 4), there have yet to be any reports relating to α-amino acid derivatives having βARK1 inhibitory activity.
Although cardiotonics, β-blockers, inhibitors of angiotensin-converting enzyme, angiotensin II antagonists and calcium antagonists and the like are currently used to treat heart failure, since cardiotonics are associated with an increased mortality rate caused by long-term administration, the effects of inhibitors of angiotensin-converting enzyme and angiotensin II antagonists are insufficient, and β-blockers have the disadvantage of requiring hospitalized monitoring due to the negative inotropic action thereof, a drug is sought that is safer and more highly effective.
On the other hand, the majority of the cells of the human body do not undergo cell division except for in the case of requiring cell regeneration such as during tissue damage. However, certain limited cells such as tumor cells proliferate at a certain frequency. Such cells are referred to as being in a “cell cycle”. The cell cycle consists of four stages in a predetermined sequence, and these are referred to as the G1 stage, S stage, G2 stage and M stage. Progression of the cell cycle is precisely controlled by various kinases such as cyclin-dependent kinase (CDK) and Aurora kinase. As the relationship between disruption of the cell cycle and tumor formation and proliferation has become clearer, the importance of cell cycle research has enhanced on the basis of it being potentially intimately involved in the essential nature of tumors. On the basis of this background, although research has conventionally been conducted on the manner in which the cell cycle progresses, the control mechanisms of the cell cycle and methods for inhibiting the cell cycle in order to elucidate the mechanism of tumors and develop pharmaceuticals, analysis of the cell cycle has recently become an important analytical tool in fields such as cell death, aging and regeneration as well.
Aurora kinase, which is a kind of serine-threonine kinase, is known to exist in the form of three types of subtypes (Aurora A, B and C) having high homology between the kinase domains of the C terminal. These subtypes are collectively referred to as the Aurora family. On the basis of previous research, the Aurora family has been determined to be essential for accurately controlling mitosis, including separation of the centromere in the mitosis stage and bipolar spindle formation (see, for example, Non-Patent Document 8). The relationship between Aurora kinase and tumors began with reports describing the over-expression of Aurora-A and Aurora-B in colon cancer (see, for example, Non-Patent Document 9), and were followed by reports indicating that Aurora-A is highly expressed in numerous tumors such as breast cancer, ovarian cancer, liver cancer, gastric cancer and pancreatic cancer. In addition, results have also been reported indicating that cancer patients in which Aurora kinase is expressed at high levels have a poor prognosis (see, for example, Non-Patent Document 10), and several Aurora kinase inhibitors are known to be currently undergoing clinical evaluation.
Cyclin-dependent kinase (CDK), which is also a serine-threonine kinase, also plays an extremely important role in regulation of the cell cycle. This kinase precisely controls the cell cycle by expressing its function as a result of forming complexes specific to the cell cycle between enzyme subunits having enzyme activity in the form of CDK1, CDK2, CDK3, CDK4 or CDK6 and activity-regulating subunits expressed specifically to the cell cycle in the form of cyclins A, B, D1, D2, D3 and E (in the present description, complexes composed of catalyst subunits in the form of CDK# and activity-regulating subunits in the form of cyclin* are represented as “CDK#/cyclin*” complexes) (see, for example, Non-Patent Document 11).
For example, CDK1/cyclin B complex is required for progression from the G2 stage to the M stage of the cell cycle, and is also required to complete mitosis (see, for example, Non-Patent Document 12). The CDK2/cyclin E complex controls progression from the G1 stage to the S stage (see, for example, Non-Patent Document 13). CDK3 is thought to function in progression to the G1 stage and although it was thought to be important in G1-S progression (see, for example, Non-Patent Document 14), according to more recent reports, cells not present in the cell stage (G0 cells) have been reported to function during progression to the G1 stage in order to initiate cell proliferation (see, for example, Non-Patent Document 15).
Mutation and high expression of CDK and cyclin genes have been frequently reported in numerous genes similar to the Aurora family. As a result, attention has been focused on CDK as well as an important target molecule for cancer therapy, and numerous pharmaceutical companies are proceeding with research and development of low molecular weight compounds targeting the ATP-binding region of CDK. These CDK inhibitors inhibit proliferation of tumor cells both in vitro and in vivo (see, for example, Non-Patent Document 16). Numerous CDK inhibitors are known to be currently undergoing clinical evaluations.
Aurora kinase inhibitors and cyclin-dependent kinase (CDK) inhibitors both inhibit proliferation of tumor cells in xenograft mouse strains loaded with human tumor cells in human tumor cell lines as well. However, since human cancers are composed of genetically and biologically heterogeneous cells, sensitivity to individual antitumor agents is known to vary for each individual cell. For this reason, in order to develop highly effective antitumor agents, instead of developing Aurora kinase inhibitors and CDK inhibitors separately, it is preferable to develop drugs that simultaneously inhibit a plurality of targets relating to cell proliferation. This is supported by the fact that numerous multi-kinase inhibitors such as sunitinib maleate (SU11248 maleate: including VEGFR-1,2,3, PDGFR, KIT, Flt3 and CSFIR), imanitib mesylate (Gleevec: including Bcr-Abl kinase, C-KIT and PDGFR) and lapanitib (including EGFR and HER2) demonstrate potent clinical effects.
There are currently no antitumor agents that have actually been released commercially in the form of dual Aurora kinase and CDK inhibitors (referred to as “Aurora/CDK dual inhibitors” in the present description). Although the only such inhibitor currently at the pre-clinical trial stage is JNJ-7706621, since it is necessary to administer this drug by consecutive daily subcutaneous injections in order to obtain the maximum effects thereof, it is predicted to encounter difficulties in clinical application in consideration of patient QOL (see, for example, Patent Document 5 and Non-Patent Document 17). Namely, there is currently no practical therapeutic drug for use in preventing or treating cancer that has Aurora/CDK dual inhibitory activity.
In addition, there are numerous drugs that simultaneously inhibit Aurora kinase and CDK known to currently be in the research stage. However, compounds having a pyrazolobenzothiazole backbone have previously not been known as compounds that simultaneously inhibit Aurora kinase and CDK.
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